Interferon-Independent Restriction of RNA Virus Entry and Replication by a Class of Damage-Associated Molecular Patterns

ABSTRACT Mammalian cells detect microbial molecules known as pathogen-associated molecular patterns (PAMPs) as indicators of potential infection. Upon PAMP detection, diverse defensive responses are induced by the host, including those that promote inflammation and cell-intrinsic antimicrobial activ...

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Autores principales:	Michael J. Ernandes, Jonathan C. Kagan
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2021
Materias:	DAMP SARS innate immunity oxPAPC virus Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/922661acc6af4886bd6183f6d1b34b20
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spelling	oai:doaj.org-article:922661acc6af4886bd6183f6d1b34b202021-11-10T18:37:48ZInterferon-Independent Restriction of RNA Virus Entry and Replication by a Class of Damage-Associated Molecular Patterns10.1128/mBio.00584-212150-7511https://doaj.org/article/922661acc6af4886bd6183f6d1b34b202021-04-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00584-21https://doaj.org/toc/2150-7511ABSTRACT Mammalian cells detect microbial molecules known as pathogen-associated molecular patterns (PAMPs) as indicators of potential infection. Upon PAMP detection, diverse defensive responses are induced by the host, including those that promote inflammation and cell-intrinsic antimicrobial activities. Host-encoded molecules released from dying or damaged cells, known as damage-associated molecular patterns (DAMPs), also induce defensive responses. Both DAMPs and PAMPs are recognized for their inflammatory potential, but only the latter are well established to stimulate cell-intrinsic host defense. Here, we report a class of DAMPs that engender an antiviral state in human epithelial cells. These DAMPs include oxPAPC (oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine), PGPC (1-palmitoyl-2-glutaryl phosphatidylcholine), and POVPC [1-palmitoyl-2-(5-oxovaleroyl)-sn-glycero-3-phosphatidylcholine], oxidized lipids that are naturally released from dead or dying cells. Exposing cells to these DAMPs prior to vesicular stomatitis virus (VSV) infection limits viral replication. Mechanistically, these DAMPs prevent viral entry, thereby limiting the percentage of cells that are productively infected and consequently restricting viral load. We found that the antiviral actions of oxidized lipids are distinct from those mediated by the PAMP Poly I:C, in that the former induces a more rapid antiviral response without the induction of the interferon response. These data support a model whereby interferon-independent defensive activities can be induced by DAMPs, which may limit viral replication before PAMP-mediated interferon responses are induced. This antiviral activity may impact viruses that disrupt interferon responses in the oxygenated environment of the lung, such as influenza virus and SARS-CoV-2. IMPORTANCE In this work, we explored how a class of oxidized lipids, spontaneously created during tissue damage and unprogrammed cell lysis, block the earliest events in RNA virus infection in the human epithelium. This gives us novel insight into the ways that we view infection models, unveiling a built-in mechanism to slow viral growth that neither engages the interferon response nor is subject to known viral antagonism. These oxidized phospholipids act prior to infection, allowing time for other, better-known innate immune mechanisms to take effect. This discovery broadens our understanding of host defenses, introducing a soluble factor that alters the cellular environment to protect from RNA virus infection.Michael J. ErnandesJonathan C. KaganAmerican Society for MicrobiologyarticleDAMPSARSinnate immunityoxPAPCvirusMicrobiologyQR1-502ENmBio, Vol 12, Iss 2 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	DAMP SARS innate immunity oxPAPC virus Microbiology QR1-502
spellingShingle	DAMP SARS innate immunity oxPAPC virus Microbiology QR1-502 Michael J. Ernandes Jonathan C. Kagan Interferon-Independent Restriction of RNA Virus Entry and Replication by a Class of Damage-Associated Molecular Patterns
description	ABSTRACT Mammalian cells detect microbial molecules known as pathogen-associated molecular patterns (PAMPs) as indicators of potential infection. Upon PAMP detection, diverse defensive responses are induced by the host, including those that promote inflammation and cell-intrinsic antimicrobial activities. Host-encoded molecules released from dying or damaged cells, known as damage-associated molecular patterns (DAMPs), also induce defensive responses. Both DAMPs and PAMPs are recognized for their inflammatory potential, but only the latter are well established to stimulate cell-intrinsic host defense. Here, we report a class of DAMPs that engender an antiviral state in human epithelial cells. These DAMPs include oxPAPC (oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine), PGPC (1-palmitoyl-2-glutaryl phosphatidylcholine), and POVPC [1-palmitoyl-2-(5-oxovaleroyl)-sn-glycero-3-phosphatidylcholine], oxidized lipids that are naturally released from dead or dying cells. Exposing cells to these DAMPs prior to vesicular stomatitis virus (VSV) infection limits viral replication. Mechanistically, these DAMPs prevent viral entry, thereby limiting the percentage of cells that are productively infected and consequently restricting viral load. We found that the antiviral actions of oxidized lipids are distinct from those mediated by the PAMP Poly I:C, in that the former induces a more rapid antiviral response without the induction of the interferon response. These data support a model whereby interferon-independent defensive activities can be induced by DAMPs, which may limit viral replication before PAMP-mediated interferon responses are induced. This antiviral activity may impact viruses that disrupt interferon responses in the oxygenated environment of the lung, such as influenza virus and SARS-CoV-2. IMPORTANCE In this work, we explored how a class of oxidized lipids, spontaneously created during tissue damage and unprogrammed cell lysis, block the earliest events in RNA virus infection in the human epithelium. This gives us novel insight into the ways that we view infection models, unveiling a built-in mechanism to slow viral growth that neither engages the interferon response nor is subject to known viral antagonism. These oxidized phospholipids act prior to infection, allowing time for other, better-known innate immune mechanisms to take effect. This discovery broadens our understanding of host defenses, introducing a soluble factor that alters the cellular environment to protect from RNA virus infection.
format	article
author	Michael J. Ernandes Jonathan C. Kagan
author_facet	Michael J. Ernandes Jonathan C. Kagan
author_sort	Michael J. Ernandes
title	Interferon-Independent Restriction of RNA Virus Entry and Replication by a Class of Damage-Associated Molecular Patterns
title_short	Interferon-Independent Restriction of RNA Virus Entry and Replication by a Class of Damage-Associated Molecular Patterns
title_full	Interferon-Independent Restriction of RNA Virus Entry and Replication by a Class of Damage-Associated Molecular Patterns
title_fullStr	Interferon-Independent Restriction of RNA Virus Entry and Replication by a Class of Damage-Associated Molecular Patterns
title_full_unstemmed	Interferon-Independent Restriction of RNA Virus Entry and Replication by a Class of Damage-Associated Molecular Patterns
title_sort	interferon-independent restriction of rna virus entry and replication by a class of damage-associated molecular patterns
publisher	American Society for Microbiology
publishDate	2021
url	https://doaj.org/article/922661acc6af4886bd6183f6d1b34b20
work_keys_str_mv	AT michaeljernandes interferonindependentrestrictionofrnavirusentryandreplicationbyaclassofdamageassociatedmolecularpatterns AT jonathanckagan interferonindependentrestrictionofrnavirusentryandreplicationbyaclassofdamageassociatedmolecularpatterns
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Interferon-Independent Restriction of RNA Virus Entry and Replication by a Class of Damage-Associated Molecular Patterns

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